u-50488 and Edema

The effect of repeated contralateral treatment with the kappa-opioid receptor agonist U-50,488H {trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzene acetamide methanesulphonate} was investigated in rats with unilaterally induced adjuvant arthritis.. Arthritis was induced by injection of Mycobacterium butyricum into the right hindpaw. Inflammatory parameters, nociceptive behaviour and cartilage turnover were evaluated up to 21 days after induction of arthritis.. Contralateral treatment with 0.3 mg U-50,488H into the left hindpaw twice per week reduced the hindpaw oedema, ankle joint inflammation, pain behaviour to mechanical stimuli and severity score of inflammation in the hindpaws of both sides as well as the systemic spread of inflammation to other areas, e.g. tail and/or forepaws, compared with saline-treated animals. Moreover, a significant decrease in the levels of cartilage oligomeric matrix protein was found in animals treated with U-50,488H, suggesting reduction of cartilage damage. The anti-inflammatory and chondroprotective effects of U-50,488H were abolished by administration of the peripheral opioid receptor antagonist naloxone methiodide.. This is the first report demonstrating that repeated contralateral administration of a kappa-opioid receptor agonist diminishes the development of a symmetrical joint disorder.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Animals; Ankle Joint; Antirheumatic Agents; Arthritis, Experimental; Body Weight; Drug Administration Schedule; Edema; Female; Hindlimb; Pain; Pain Measurement; Rats; Rats, Inbred Lew; Receptors, Opioid, kappa; Severity of Illness Index

We evaluated the anti-exudative effects (Evan's blue) of mu-, delta- and kappa-opioid receptor agonists in a rat model of carrageenan-induced acute inflammation. The contribution of different components was assessed after the administration of: cyclosporine A, capsaicin, 6-hydroxydopamine, compound 48/80, and specific histamine-receptor antagonists. The results show that the mu-opioid receptor agonists morphine and fentanyl and the delta-opioid receptor agonists DPDPE (enkephalin, [D-Pen(2,5)]) and SNC 80 ((+)-4-[(alpha R)-alpha((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N diethylbenzamide) decrease plasma extravasation in a dose-dependent manner, with a biphasic response. The effects were reversed by specific antagonists, and are predominantly mediated by peripheral opioid receptors. The integrity of sensory and sympathetic fibres is essential for the anti-exudative effects of fentanyl and DPDPE. Histamine and functional histamine H(2) and H(3) receptors are required for morphine and fentanyl (but not DPDPE) inhibition of plasma extravasation, suggesting different mechanism for mu- and delta-opioid receptor agonists. The present findings implicate multiple sites and mechanisms in the anti-exudative effects of exogenous opioids.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Non-Narcotic; Analgesics, Opioid; Animals; Benzamides; Capsaicin; Carrageenan; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Enkephalin, D-Penicillamine (2,5)-; Extravasation of Diagnostic and Therapeutic Materials; Fentanyl; Hindlimb; Histamine Antagonists; Inflammation; Male; Morphine; Narcotic Antagonists; Oxidopamine; p-Methoxy-N-methylphenethylamine; Piperazines; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

U-50488H, a selective opioid kappa receptor agonist has been shown to be a neuroprotective agent in animal models of spinal cord injury. The mechanism of action of U-50488H is not known. Methylprednisolone, the only neuroprotective drug proven in patients with acute spinal cord injury may prevent the secondary injury after an initial trauma. Secondary vascular injury develops after experimental spinal cord trauma. In this study we examined the effects of U-50488H on post-traumatic vascular injury based on the measurement of vascular permeability, edema and neutrophil infiltration in a rat spinal cord injury model. Vascular permeability was assessed by vascular extravasation of fluorescein isothiocyanate conjugated dextran (FITC-D), a macromolecular tracer. Tissue edema was determined by percentage water content and neutrophil infiltration by myeloperoxidase (MPO) activity, a marker enzyme for neutrophils. U-50488H at doses of 5, 10, 20 and 40 mg/kg i.p. administered twice (0.5 h before and 0.5 h after trauma) reduced vascular permeability in a dose-dependent manner. More frequent dosing (10 mg/kg, 0.5 h before and 0.5, 2, 8 and 22 h after injury) reduced vascular permeability 24 h after injury. U-50488H also reduced edema formation but did not affect neutrophil infiltration. Results from this study raise the possibility that the neuroprotective effect of U-50488H involves a secondary vascular event.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Blood Vessels; Capillary Permeability; Disease Models, Animal; Edema; Female; Neutrophils; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Spinal Cord Injuries